Control of metabolism

ABSTRACT

A compound of formula I                    
     or a pharmaceutically acceptable salt thereof in which R 1  and R 2  are independently H or methyl (for example N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl ]-3-methylbutyl amine hydrochloride optionally in the form of its monohydrate) is used for treating metabolic disorders, such as increased non-exercise activity thermogenesis or increased metabolic rate.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/125,117, filed Mar. 19, 1999, now abandoned.

This invention relates to a method of controlling metabolism.

According to the present invention there is provided a method oftreating metabolic disorders, in which a therapeutically effectiveamount of a compound of formula I

including enantiomers and pharmaceutically acceptable salts thereof, inwhich R₁ and R₂ are independently H or methyl, is administered inconjunction with a pharmaceutically acceptable diluent or carrier to ahuman in need thereof.

Metabolic diseases which may advantageously be treated with a compoundof formula I include increased non-exercise activity thermogenesis andincreased metabolic rate.

A preferred compound of formula I isN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine or asalt thereof, for example the hydrochloride salt. A preferred form ofthis hydrochloride is its monohydrate.

The preparation and use of compounds of formula I, such asN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine,N-{1-[1-(4-chlorophenyl)-cyclobutyl]-3-methylbutyl}-N-methylamine, and1-[1-(4-chlorophenyl)-cyclobutyl]-3-methylbutylamine and salts thereof,in the treatment of depression is described in British PatentSpecification 2098602 and U.S. Pat. No. 4,522,828. The use of compoundsof formula I such as N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and salts thereof in the treatment ofParkinson's disease is described in published PCT application WO88/06444. The use ofN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine andsalts thereof in the treatment of cerebral function disorders isdescribed in U.S. Pat. No. 4,939,175. The use ofN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride in the treatment of obesity is described in published PCTapplication WO90/061 10. A particularly preferred form of this compoundis N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride monohydrate (sibutramine hydrochloride) which is describedin European Patent Number 230742. The use ofN,N-dimethyl-1-[l-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine andsalts thereof for improving the glucose tolerance of humans havingImpaired Glucose Tolerance or Non-Insulin Dependent Diabetes Mellitus isdescribed in published PCT application WO95/20949.

It will be appreciated by those skilled in the art that compounds offormula I contain a chiral centre. When a compound of formula I containsa single chiral centre it may exist in two enantiomeric forms. Thepresent invention includes the use of the individual enantiomers andmixtures of the enantiomers. The enantiomers may be resolved by methodsknown to those skilled in the art, for example by formation ofdiastereoisomeric salts or complexes which may be separated, forexample, by crystallisation; via formation of diastereoisomericderivatives which may be separated, for example, by crystallisation,gas-liquid or liquid chromatography; selective reaction of oneenantiomer with an enantiomer-specific reagent, for example enzymaticoxidation or reduction, followed by separation of the modified andunmodified enantiomers; or gas-liquid or liquid chromatography in achiral environment, for example on a chiral support, for example silicawith a bound chiral ligand or in the presence of a chiral solvent. Itwill be appreciated that where the desired enantiomer is converted intoanother chemical entity by one of the separation procedures describedabove, a further step is required to liberate the desired enantiomericform. Alternatively, specific enantiomers may be synthesised byasymmetric synthesis using optically active reagents, substrates,catalysts or solvents, or by converting one enantiomer to the other byasymmetric transformation.

Preferred compounds of formula I areN,N-dimethyl-1-[1-(4-chlorophenyl)-cyclobutyl]-3-methylbutylamine,N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-methylamine, and1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine including racemates,individual enantiomers and mixtures thereof, and pharmaceuticallyacceptable salts thereof.

The individual enantiomers can be prepared by enantioselective synthesisfrom optically active precursors, or by resolving the racemic compoundwhich can be prepared as described above. Enantiomers of secondaryamines of the formula I can also be prepared by preparing the racemateof the corresponding primary amine, resolving the latter into theindividual enantiomers, and then converting the optically pure primaryamine enantiomer into the required secondary amine by methods describedin British Patent Specification 2098602.

Specific examples of compounds of formula I are:

(+)-N-[1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-methylamine;

(−)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-methylamine;

(+)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine;

(−)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine;

(+)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-N-dimethylamine;

(−)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-N-dimethylamine.

The hydrochloride salts are preferred in each case, but the free basesand other pharmaceutically acceptable salts are also suitable.

The compound of formula I may be administered in any of the knownpharmaceutical dosage forms. The amount of the compound to beadministered will depend on a number of factors including the age of thepatient, the severity of the condition and the past medical history ofthe patient and always lies within the sound discretion of theadministering physician but it is generally envisaged that the dosage ofthe compound to be administered will be in the range 0.1 to 50 mgpreferably 1 to 30 mg per day given in one or more doses.

Oral dosage forms are the preferred compositions for use in the presentinvention and these are the known pharmaceutical forms for suchadministration, for example tablets, capsules, granules, syrups andaqueous or oil suspensions. The excipients used in the preparation ofthese compositions are the excipients known in the pharmacist's art.Tablets may be prepared from a mixture of the active compound withfillers, for example calcium phosphate; disintegrating agents, forexample maize starch; lubricating agents, for example magnesiumstearate; binders, for example microcrystalline cellulose orpolyvinylpyrrolidone and other optional ingredients known in the art topermit tableting the mixture by known methods. The tablets may, ifdesired, be coated using known methods and excipients which may includeenteric coating using for example hydroxypropylmethylcellulosephthalate. The tablets may be formulated in a manner known to thoseskilled in the art so as to give a sustained release of the compounds ofthe present invention. Such tablets may, if desired, be provided withenteric coatings by known methods, for example by the use of celluloseacetate phthalate. Similarly, capsules, for example hard or soft gelatincapsules, containing the active compound with or without addedexcipients, may be prepared by known methods and, if desired, providedwith enteric coatings in a known manner. The contents of the capsule maybe formulated using known methods so as to give sustained release of theactive compound. The tablets and capsules may conveniently each contain1 to 50 mg of the active compound.

Other dosage forms for oral administration include, for example, aqueoussuspensions containing the active compound in an aqueous medium in thepresence of a non-toxic suspending agent such as sodiumcarboxymethylcellulose, and oily suspensions containing a compound ofthe present invention in a suitable vegetable oil, for example arachisoil. The active compound may be formulated into granules with or withoutadditional excipients. The granules may be ingested directly by thepatient or they may be added to a suitable liquid carrier (for example,water) before ingestion. The granules may contain disintegrants, eg aneffervescent couple formed from an acid and a carbonate or bicarbonatesalt to facilitate dispersion in the liquid medium.

The therapeutically active compounds of formula I may be formulated intoa composition which the patient retains in his mouth so that the activecompound is administered through the mucosa of the mouth.

Dosage forms suitable for rectal administration are the knownpharmaceutical forms for such administration, for example, suppositorieswith cocoa butter or polyethylene glycol bases.

Dosage forms suitable for parenteral administration are the knownpharmaceutical forms for such administration, for example sterilesuspensions or sterile solutions in a suitable solvent.

Dosage forms for topical administration may comprise a matrix in whichthe pharmacologically active compounds of the present invention aredispersed so that the compounds are held in contact with the skin inorder to administer the compounds transdermally. A suitable transdermalcomposition may be prepared by mixing the pharmaceutically activecompound with a topical vehicle, such as a mineral oil, petrolatumand/or a wax, e.g. paraffin wax or beeswax, together with a potentialtransdermal accelerant such as dimethyl sulphoxide or propylene glycol.Alternatively the active compounds may be dispersed in apharmaceutically acceptable cream, gel or ointment base. The amount ofactive compound contained in a topical formulation should be such that atherapeutically effective amount of the compound is delivered during theperiod of time for which the topical formulation is intended to be onthe skin.

The therapeutically active compound of formula I may be formulated intoa composition which is dispersed as an aerosol into the patients oral ornasal cavity. Such aerosols may be administered from a pump pack or froma pressurised pack containing a volatile propellant.

The therapeutically active compounds of formula I used in the method ofthe present invention may also be administered by continuous infusioneither from an external source, for example by intravenous infusion orfrom a source of the compound placed within the body. Internal sourcesinclude implanted reservoirs containing the compound to be infused whichis continuously released for example by osmosis and implants which maybe (a) liquid such as an oily suspension of the compound to be infusedfor example in the form of a very sparingly water-soluble derivativesuch as a dodecanoate salt or a lipophilic ester or (b) solid in theform of an implanted support, for example of a synthetic resin or waxymaterial, for the compound to be infused. The support may be a singlebody containing all the compound or a series of several bodies eachcontaining part of the compound to be delivered. The amount of activecompound present in an internal source should be such that atherapeutically effective amount of the compound is delivered over along period of time.

In some formulations it may be beneficial to use the compounds of thepresent invention in the form of particles of very small size, forexample as obtained by fluid energy milling.

In the compositions of the present invention the active compound may, ifdesired, be associated with other compatible pharmacologically activeingredients.

The invention further provides the use of compounds of formula I in themanufacture of a medicament for treating metabolic disorders, forexample increased non-exercise activity thermogenesis and increasedmetabolic rate.

In another aspect, the invention further provides a pharmaceuticalcomposition for increased non-exercise activity thermogenesis orincreased metabolic rate, comprising a compound of formula I inconjunction with a pharmaceutically acceptable diluent or carrier.

Monoamine reuptake inhibitors have been used to treat certain of thedisorders described in the present invention. However, these compoundsare known to suffer from a number of disadvantages. Firstly suchcompounds are not effective in all patients. Secondly where thecompounds are effective they may not provide a complete cure of thedisorder. Thirdly, there are many undesirable side-effects known withthis type of compound. Such side-effects include nausea, sexualdysfunction, light headedness, somnolence, sweating, tremor, dry mouth,asthenia, insomnia, diarrhoea, headache, vomiting, anxiety, drowsiness,dizziness, fever, rash or allergic reactions, arthralgia, myalgia,convulsions, hypomania and mania.

Sibutramine (Formula I, R₁═CH₃, R₂═CH₃) has a pharmacological profilewhich is unique amongst monoamine reuptake inhibitors. Through itspharmacologically active metabolites, (metabolite 1, R₁═H, R₂═CH₃ inFormula I and metabolite 2, R₁═H, R₂═H in Formula I) sibutramineinhibits the reuptake of all three monoamines differentiating it fromserotonin (5-HT)-selective reuptake inhibitors, e.g. fluoxetine,noradenaline-selective reuptake inhibitors, e.g. desipramine,dopamine-selective reuptake inhibitors, e.g. bupropion, andserotonin-noradenaline reuptake inhibitors, e.g. venlafaxine (Table 1).It is this unique combination of pharmacological actions which renderssibutramine, and the other compounds of formula I, efficacious in amethod of controlling metabolism.

The assays below are performed in a similar manner to those described inWO98/41528.

TABLE Comparison of the in vitro monoamine reuptake inhibition profilesof Examples 1 and 2, and various reference monoamine reuptake inhibitorsin rat brain tissue Ki (nM) [³H]Noradenaline [³H]5-HT [³H]DopamineExample 1 3 18 24 Example 2 5 26 31 Bupropion 2590 18312 409 Desipramine2 200 4853 Fluoxetine 320 11 2025 Venlafaxine 196 26 2594

The results are the means of ≧3 separate determinations

EXAMPLE 1 R₁═H, R₂═CH₃ in Formula I EXAMPLE 2 R₁═H, R₂═H in Formula I

The efficacy of compounds of formula I in treating metabolic disordersis demonstrable through clinical trials in a relevant population set.

The invention has been described with reference to various specificembodiments. However, many variations and modifications may be madewhile remaining within the scope and spirit of the invention.

What is claimed is:
 1. A method of treating increased non-exerciseactivity thermogenesis and increased metabolic rate comprisingadministering to a human in need thereof a therapeutically effectiveamount of a compound of formula 1,

an enantiomer or a pharmaceutically acceptable salt thereof in which R₁and R₂ are independently H or methyl, in conjunction with apharmaceutically acceptable diluent or carrier.
 2. The method as claimedin claim 1 wherein the compound of formula 1 isN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride.
 3. The method as claimed in claim 1 wherein the compoundof formula 1 isN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride in the form of its monohydrate.
 4. The method as claimedin claim 1 wherein the compound of formula 1 is(+)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-methylamine. 5.The method as claimed in claim 1 wherein the compound of formula 1 is(−)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-methylamine. 6.The method as claimed in claim 1 wherein the compound of formula 1 is(+)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine.
 7. The methodas claimed in claim 1 wherein the compound of formula 1 is(−)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine.
 8. The methodas claimed in claim 1 wherein the compound of formula 1 is(+)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-N-dimethylamine.9. The method as claimed in claim 1 wherein the compound of formula I is(−)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-N-dimethylamine.10. The method as claimed in claim 1 wherein the compound of formula Iis (±)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-methylamine.11. The method as claimed in claim 1 wherein the compound of formula Iis (±)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine.
 12. Themethod as claimed in claim 1 wherein the compound of formula I is(±)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-N-dimethylamine.